Advanced Drug Delivery Reviews 64 (2012) 4960

Contents lists available at SciVerse ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Environment-sensitive hydrogels for drug delivery

Yong Qiu, Kinam Park
Departments of Pharmaceutics and Biomedical Engineering, Purdue University, West Lafayette, IN 47907-1336, USA

a r t i c l e

i n f o

Article history:
Received 14 August 2001
Available online 13 September 2012
Keywords:
Environment-sensitive hydrogels
Drug delivery
Stimuli-sensitive hydrogels
Smart hydrogels

a b s t r a c t
Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental
variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive
and/or temperature-sensitive hydrogels can be used for site-specic controlled drug delivery. Hydrogels that are
responsive to specic molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery
systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used
in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the
practical applications require signicant improvements in the hydrogel properties. The most signicant weakness
of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels
are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually
makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications.
Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new
polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful
applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If
the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive
hydrogels with a wide array of desirable properties can be made.
2012 Elsevier B.V. All rights reserved.

Contents
1.
2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . .
Temperature-sensitive hydrogels . . . . . . . . . . . . . . .
2.1.
Polymer structures . . . . . . . . . . . . . . . . . .
2.2.
Properties of temperature-sensitive hydrogels . . . . .
2.3.
Applications of temperature-sensitive hydrogels . . . .
2.3.1.
Negatively thermosensitive drug release systems
2.3.2.
Positively thermosensitive drug release systems
2.3.3.
Thermoreversible gels . . . . . . . . . . . .
2.4.
Limitations and improvements . . . . . . . . . . . .
pH-sensitive hydrogels . . . . . . . . . . . . . . . . . . .
3.1.
Polymer structures . . . . . . . . . . . . . . . . . .
3.2.
Properties of pH-sensitive hydrogels . . . . . . . . . .
3.3.
Applications of pH-sensitive hydrogels . . . . . . . . .
3.3.1.
Controlled drug delivery . . . . . . . . . . .
3.3.2.
Other applications . . . . . . . . . . . . . .
3.4.
Limitations and improvements . . . . . . . . . . . .
Glucose-sensitive hydrogels . . . . . . . . . . . . . . . . .
4.1.
pH-sensitive membrane systems . . . . . . . . . . . .
4.2.
Con A-immobilized systems . . . . . . . . . . . . . .

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Abbreviations: IPN, interpenetrating polymer network; LCST, lower critical solution temperature; PAAm, poly(acrylamide); BMA, butyl methacrylate; PNIAAm,
poly(N-isopropylacrylamide); PDEAAm, poly(N,N-diethylacrylamide); PEG, poly(ethylene glycol); PEO, poly(ethylene oxide); PPO, poly(propylene oxide); poly(acrylic acid),
poly(acrylic acid); PMA, poly(methacrylic acid); PLA, poly(L-lactic acid); PDEAEM, poly(N,N-diethylaminoethyl methacrylate); DMAEM, N,N-dimethylaminoethyl methacrylate; PVD,
poly(vinylacetaldiethylaminoacetate); PVA, poly(vinylalcohol); Con A, concanavalin A.
PII of original article: S0169-409X(01)00203-4. The article was originally published in Advanced Drug Delivery Reviews 53 (2001) 321339.
Corresponding author. Tel.: +1 765 494 7759; fax: +1 765 496 1903.
E-mail address: kpark@purdue.edu (K. Park).
0169-409X/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.addr.2012.09.024

50

Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

4.3.
Solgel phase reversible hydrogel systems . . .
4.4.
Limitations and improvements . . . . . . . . .
5.
Electric signal-sensitive hydrogels . . . . . . . . . . .
5.1.
Properties of electro-sensitive hydrogels . . . .
5.2.
Applications of electro-sensitive hydrogels . . .
5.2.1.
Applications in drug delivery . . . . .
5.2.2.
Applications in other areas . . . . . .
5.2.3.
Limitations and improvements . . . .
6.
Light-sensitive hydrogels . . . . . . . . . . . . . . .
6.1.
Properties of light-sensitive hydrogels . . . . .
6.2.
Applications . . . . . . . . . . . . . . . . .
6.3.
Limitations and improvements . . . . . . . . .
7.
Other stimuli sensitive hydrogels . . . . . . . . . . .
7.1.
Pressure-sensitive hydrogels . . . . . . . . . .
7.2.
Specic ion-sensitive hydrogels . . . . . . . .
7.3.
Specic antigen-responsive hydrogels . . . . .
7.4.
Thrombin-induced infection-responsive hydrogels
8.
Summary . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
Controlled drug delivery systems, which are intended to deliver
drugs at predetermined rates for predened periods of time, have
been used to overcome the shortcomings of conventional drug formulations. Although signicant progress has been made in the controlled
drug delivery area, more advances are yet to be made for treating
many clinical disorders, such as diabetes and rhythmic heart disorders.
In these cases, the drug has to be delivered in response to uctuating
metabolic requirements or the presence of certain biomolecules in the
body. In fact, it would be most desirable if the drugs could be administered in a manner that precisely matches physiological needs at proper
times (temporal modulation) and/or at the proper site (site-specic
targeting). In addition, the controlled drug delivery area needs further
development of techniques for delivery of peptide and protein drugs.
In the body, the appearance of numerous bioactive peptides is tightly
controlled to maintain a normal metabolic balance via a feedback system called homeostasis [1]. It would be highly benecial if the active
agents were delivered by a system that sensed the signal caused by disease, judged the magnitude of signal, and then acted to release the right
amount of drug in response. Such a system would require coupling of
the drug delivery rate with the physiological need by means of some
feedback mechanism.
Hydrogels have been used extensively in the development of the
smart drug delivery systems. A hydrogel is a network of hydrophilic
polymers that can swell in water and hold a large amount of water
while maintaining the structure. A three-dimensional network is
formed by crosslinking polymer chains. Crosslinking can be provided
by covalent bonds, hydrogen bonding, van der Waals interactions, or
physical entanglements [2,3]. Hydrogels can protect the drug from
hostile environments, e.g. the presence of enzymes and low pH in
the stomach. Hydrogels can also control drug release by changing
the gel structure in response to environmental stimuli. Hydrogels
containing such sensor properties can undergo reversible volume
phase transitions or gelsol phase transitions upon only minute
changes in the environmental condition. The types of environmentsensitive hydrogels are also called Intelligent or smart hydrogels
[4]. Many physical and chemical stimuli have been applied to induce
various responses of the smart hydrogel systems. The physical stimuli
include temperature, electric elds, solvent composition, light, pressure,
sound and magnetic elds, while the chemical or biochemical stimuli
include pH, ions and specic molecular recognition events [5,6]. Smart
hydrogels have been used in diverse applications, such as in making articial muscles [711], chemical valves [12], immobilization of enzymes
and cells [1321], and concentrating dilute solutions in bioseparation

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[2227]. Environment-sensitive hydrogels are ideal candidates for

developing self-regulated drug delivery systems. For convenience,
environment-sensitive hydrogels are classied based on the type of
stimuli in this chapter.
2. Temperature-sensitive hydrogels
2.1. Polymer structures
Temperature-sensitive hydrogels are probably the most commonly studied class of environmentally sensitive polymer systems
in drug delivery research [28]. Many polymers exhibit a temperatureresponsive phase transition property. The structures of some of
those polymers are shown in Fig. 1. The common characteristic of
temperature-sensitive polymers is the presence of hydrophobic groups,
such as methyl, ethyl and propyl groups. Of the many temperaturesensitive polymers, poly(N-isopropylacrylamide) (PNIPAAm) is probably
the most extensively used. Poly(N,N-diethylacrylamide (PDEAAm) is also
widely used because of its lower critical solution temperature (LCST) in
the range of 2532 C, close to the body temperature. Copolymers of
NIPAAm can also be made using other monomers, e.g. butyl methacrylate
(BMA), to alter the LCST.
Certain types of block copolymers made of poly(ethylene oxide)
(PEO) and poly(propylene oxide) (PPO) also possess an inverse temperature sensitive property. Because of their LCST at around the body temperature, they have been used widely in the development of controlled
drug delivery systems based on the solgel phase conversion at the body
temperature. A large number of PEOPPO block copolymers are commercially available under the names of Pluronics (or Poloxamers)
and Tetronics. Their structures are shown in Fig. 2.
2.2. Properties of temperature-sensitive hydrogels
Most polymers increase their water-solubility as the temperature increases. Polymers with LCST, however, decrease their water-solubility
as the temperature increases. Hydrogels made of LCST polymers shrink
as the temperature increases above the LCST. This type of swelling behavior is known as inverse (or negative) temperature-dependence. The
inverse temperature-dependent hydrogels are made of polymer chains
that either possess moderately hydrophobic groups (if too hydrophobic,
the polymer chains would not dissolve in water at all) or contain a
mixture of hydrophilic and hydrophobic segments. At lower temperatures, hydrogen bonding between hydrophilic segments of the polymer
chain and water molecules are dominates, leading to enhanced dissolution in water. As the temperature increases, however, hydrophobic

Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

51

Fig. 1. Structures of some temperature-sensitive polymers.

interactions among hydrophobic segments become strengthened,

while hydrogen bonding becomes weaker. The net result is shrinking
of the hydrogels due to inter-polymer chain association through hydrophobic interactions. In general, as the polymer chain contains more
hydrophobic constituent, LCST becomes lower [29]. The LCST can be
changed by adjusting the ratio of hydrophilic and hydrophobic segment
of the polymer. One way is to make copolymers of hydrophobic
(e.g. NIPAAm) and hydrophilic (e.g. acrylic acid) monomers [2932].
The continuous phase transition of PNIPAAm is known to be changed
to a discontinuous one by incorporating a small amount of ionizable
groups into the gel network [33,34] or by changing solvent composition
[35]. Copolymerization of NIPAAm with different types of monomers
results in hydrogels with more versatile properties, such as faster
rates of shrinking when heated through the LCST [36], and sensitivity
to additional stimuli.
If the polymer chains in hydrogels are not covalently crosslinked,
temperature-sensitive hydrogels may undergo solgel phase transitions, instead of swellingshrinking transitions. The thermally reversible gels with inverse temperature dependence become sol at higher
temperatures. Polymers that show this type of behavior are block copolymers of PEO and PPO as shown in Fig. 2. The hydrophobic PPO block
can be replaced with other hydrophobic polymers. For example, PEOcontaining block copolymers with poly(lactic acid) show the same
thermo-reversible behavior. In this case, the poly(lactic acid) segment
provides a biodegradable property.
Temperature-sensitive hydrogels can also be made using
temperature-sensitive crosslinking agents. A hybrid hydrogel system was assembled from water-soluble synthetic polymers and a
well-dened protein-folding motif, the coiled coil [37]. The hydrogel

underwent temperature-induced collapse due to the cooperative conformational transition. Using temperature-sensitive crosslinking agents
adds a new dimension in designing temperature-sensitive hydrogels.
2.3. Applications of temperature-sensitive hydrogels
Temperature-sensitive hydrogels have been studied most extensively
and their unique applications have been reviewed in depth before
[1,15,28,29,31,32]. For convenience, temperature-sensitive hydrogels
are classied into negatively thermosensitive, positively thermosensitive,
and thermally reversible gels.
2.3.1. Negatively thermosensitive drug release systems
Thermosensitive monolithic hydrogels were used to obtain an
onoff drug release prole in response to a stepwise temperature
change [3840]. The hydrogels used in these studies include crosslinked
P(NIPAAmco-BMA) hydrogels [4042], and interpenetrating polymer
networks (IPNs) of P(NIPAAm) and poly(tetramethyleneether glycol)
(PTMEG). Hydrophobic comonomer BMA was introduced into NIPAAm
gels to increase their mechanical strength. The onoff release prole of
indomethacin from these matrices was achieved with on at low temperature and off at high temperature. It was explained by the formation of a
dense, less permeable surface layer of gel, described as a skin-type barrier.
The skin barrier was formed upon a sudden temperature change due to
the faster collapse of the gel surface than the interior. This surface shrinking process was found to be regulated by the length of the methacrylate
alkyl side-chain, i.e. the hydrophobicity of the comonomer [43,44]. The
results also suggested that the drug in the polymeric matrices diffused

Fig. 2. Polymer structures of Pluronic, Pluronic R, Tetronic and Tetronic R.

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Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

from the inside to the surface during the off state even when no drug
release was seen.
Temperature-sensitive hydrogels can also be placed inside a rigid
capsule containing holes or apertures. As shown in Fig. 3, the onoff
release is achieved by the reversible volume change of temperaturesensitive hydrogels [45,46]. Such a device is called a squeezing hydrogel device because the drug release is affected by the hydrogel dimension. In addition to temperature, hydrogels can be made to respond to
other stimuli, such as pH. In this type of system, the drug release rate
was found to be proportional to the rate of squeezing of the drugloaded polymer.
Temperature-sensitive hydrogels can be secured by placing them
inside a rigid matrix or by grafting them to the surface of rigid membranes. A composite membrane was prepared by dispersing PNIPAAm
hydrogel microparticles into a crosslinked gelatin matrix [47]. The
release of a model drug, 4-acetamidophen, was dependent on the temperature which determined the swelling status of the PNIPAAm hydrogel microparticles in the microchannels of the membrane. A similar
approach was used to develop a reservoir type microcapsule drug delivery system by encapsulating the drug core with ethylcellulose containing
nano-sized PNIPAAm hydrogel particles [48]. For making stable thermally controlled onoff devices, PNIPAAm hydrogel can be grafted onto the
entire surface of a rigid porous polymer membrane [49].
2.3.2. Positively thermosensitive drug release systems
Certain hydrogels formed by IPNs show positive thermosensitivity,
i.e. swelling at high temperature and shrinking at low temperature.
IPNs of poly(acrylic acid) and polyacrylamide (PAAm) or P(AAm
co-BMA) have positive temperature dependence of swelling [50].
Increasing the BMA content shifted the transition temperature to higher
temperature. The swelling of those hydrogels was reversible, responding
to stepwise temperature changes. This resulted in reversible changes in
the release rate of a model drug, ketoprofen, from a monolithic device.
2.3.3. Thermoreversible gels
The most commonly used thermoreversible gels are Pluronics
and Tetronics . Some of them have been approved by FDA and EPA
for applications in food additives, pharmaceutical ingredients and agricultural products. A review on the properties and applications of
Pluronics in drug delivery is available [28]. For parenteral application
of thermoreversible gels, it is most desirable that they are biodegradable. To add biodegradable capacity, the PPO segment of PEOPPO
PEO block copolymers is often replaced by a biodegradable poly(L-lactic
acid) segment [5153]. The molecular architecture was not limited to the
ABA type block copolymer, but expanded into three-dimensional,
hyperbranched structures, such as a star-shaped structure. Proper combinations of molecular weight and polymer architecture resulted in
gels with different LCST values. When the hydrogel was formed
by injecting the polymer solution loaded with model drugs into a
37 C aqueous environment, the release of a hydrophilic model

Fig. 3. Schematic illustration of onoff release from a squeezing hydrogel device for
drug delivery (from Ref. [46]).

drug (ketoprofen) and a hydrophobic model drug (spironolactone)

were rst-order and S-shaped, respectively.
2.4. Limitations and improvements
Clinical applications of thermosensitive hydrogels based on NIPAAm
and its derivatives have limitations. The monomers and crosslinkers
used in the synthesis of the hydrogels are not known to be biocompatible, i.e. they may be toxic, carcinogenic or teratogenic. In addition, the
polymers of NIPAAm and its derivatives are not biodegradable. The
observation that acrylamide-based polymers activate platelets upon contact with blood, together with the unclear metabolism of poly(NIPAAm),
requires extensive toxicity studies before clinical applications can emerge
[28]. Further development of new, biocompatible and biodegradable
thermoreversible gels, such as PEOPLA block copolymers, is necessary
to exploit the useful properties of thermoreversible hydrogels.
3. pH-sensitive hydrogels
3.1. Polymer structures
All the pH-sensitive polymers contain pendant acidic (e.g. carboxylic
and sulfonic acids) or basic (e.g. ammonium salts) groups that
either accept or release protons in response to changes in environmental pH. The polymers with a large number of ionizable groups
are known as polyelectrolytes. Fig. 4 shows structures of examples
of anionic and cationic polyelectrolytes and their pH-dependent ionization. Poly(acrylic acid) (PAA) becomes ionized at high pH, while
poly(N,N-diethylaminoethyl methacrylate) (PDEAEM) becomes ionized at low pH. As shown in Fig. 4, cationic polyelectrolytes, such as
PDEAEM, dissolve more, or swell more if crosslinked, at low pH due to
ionization. On the other hand, polyanions, such as PAA, dissolve more
at high pH.
3.2. Properties of pH-sensitive hydrogels
Hydrogels made of crosslinked polyelectrolytes display big differences in swelling properties depending on the pH of the environment.
The pendant acidic or basic groups on polyelectrolytes undergo ionization just like acidic or basic groups of monoacids or monobases.
Ionization on polyelectrolytes, however, is more difcult due to electrostatic effects exerted by other adjacent ionized groups. This tends
to make the apparent dissociation constant (Ka) different from that
of the corresponding monoacid or monobase. The presence of ionizable groups on polymer chains results in swelling of the hydrogels
much beyond that can be achievable by nonelectrolyte polymer
hydrogels. Since the swelling of polyelectrolyte hydrogels is mainly
due to the electrostatic repulsion among charges present on the polymer chain, the extent of swelling is inuenced by any condition that

Fig. 4. pH-dependent ionization of polyelectrolytes. Poly(acrylic acid) (top) and

poly(N,N-diethylaminoethyl methacrylate) (bottom).

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53

reduce electrostatic repulsion, such as pH, ionic strength, and type of

counterions [54]. The swelling and pH-responsiveness of polyelectrolyte hydrogels can be adjusted by using neutral comonomers, such as
2-hydroxyethyl methacrylate, methyl methacrylate and maleic
anhydride [5558]. Different comonomers provide different hydrophobicity to the polymer chain, leading to different pH-sensitive behavior.
Hydrogels made of poly(methacrylic acid) (PMA) grafted with
poly(ethylene glycol) (PEG) have unique pH-sensitive properties [59].
At low pH, the acidic protons of the carboxyl groups of PMA interact
with the ether oxygen of PEG through hydrogen bonding, and such complexation results in shrinkage of the hydrogels. As the carboxyl groups of
PMA become ionized at high pH, the resulting decomplexation leads to
swelling of the hydrogels. The same principle can be applied to IPN systems where two different types of polymer chain interact through
pH-dependent hydrogen bonding.
3.3. Applications of pH-sensitive hydrogels
3.3.1. Controlled drug delivery
pH-sensitive hydrogels have been most frequently used to develop controlled release formulations for oral administration. The pH in
the stomach (b3) is quite different from the neutral pH in the intestine, and such a difference is large enough to elicit pH-dependent behavior of polyelectrolyte hydrogels. For polycationic hydrogels, the
swelling is minimal at neutral pH, thus minimizing drug release
from the hydrogels. This property has been used to prevent release
of foul-tasting drugs into the neutral pH environment of the mouth.
When caffeine was loaded into hydrogels made of copolymers of methyl methacrylate and N,N-dimethylaminoethylmethacrylate (DMAEM),
it was not released at neutral pH, but released at zero-order at pH 35
where DMAEM became ionized [60]. Polycationic hydrogels in the
form of semi-IPN have also been used for drug delivery in the stomach.
Semi-IPN of crosslinked chitosan and PEO showed more swelling under
acidic conditions (as in the stomach). This type of hydrogels would be
ideal for localized delivery of antibiotics, such as amoxicillin and metronidazole, in the stomach for the treatment of Helicobacter pylori [61].
Hydrogels made of PAA or PMA can be used to develop formulations
that release drugs in a neutral pH environment [57,58]. Hydrogels made
of polyanions (e.g. PAA) crosslinked with azoaromatic crosslinkers were
developed for colon-specic drug delivery. Swelling of such hydrogels
in the stomach is minimal and thus, the drug release is also minimal.
The extent of swelling increases as the hydrogel passes down the intestinal tract due to increase in pH leading to ionization of the carboxylic
groups. But, only in the colon, can the azoaromatic cross-links of the
hydrogels be degraded by azoreductase produced by the microbial
ora of the colon [62,63], as shown in Fig. 5. The degradation kinetics
and degradation pattern (e.g. surface erosion or bulk erosion) can be
controlled by the crosslinking density [62]. The kinetics of hydrogel
swelling can be controlled by changing the polymer composition [63].
The polymer composition can be changed as the pH of the environment
changes. Some pendant groups, such as N-alkanoyl (e.g. propionyl,
hexanoyl and lauroyl) and O-acylhydroxylamine moieties, can be
hydrolyzed as the pH changes from acidic to neutral values, and the
rate of side-chain hydrolysis is dependent on the length of the alkyl
moiety.
pH-sensitive hydrogels were placed inside capsules [46] or silicone
matrices [64,65] to modulate the drug release. In the squeezing hydrogel system [46], drug release was controlled by a mechanism similar to
that shown in Fig. 3. The only difference is that the swellingshrinking
of hydrogels is controlled by changing pH, instead of temperature. In
the silicone matrix system [64,65], medicated pH-dependent hydrogel
particles made of semi-IPN of PAA and PEO were used. The release patterns of several model drugs having different aqueous solubilities and
partitioning properties (including salicylamide, nicotinamide, clonidine
HCl and prednisolone) were correlated with the pH-dependent swelling
pattern of the semi-IPN. At pH 1.2, the network swelling was low and

Fig. 5. Schematic illustration of oral colon-specic drug delivery using biodegradable

and pH-sensitive hydrogels. The azoaromatic moieties in the cross-links are designated
by N_N; from Ref. [62].

the release was limited to an initial burst. At pH 6.8, the network became ionized and higher swelling resulted in increased release.
Poly(vinylacetaldiethylaminoacetate) (PVD) has pH-dependent
aqueous solubility. Both the turbidity and SEM results showed that
PVD formed a hydrogel upon increase in pH from 4 to 7.4 [66]. The
release of a model drug, chlorpheniramine maleate, was fast right
after the PVD solution was introduced into a pH 7.4 buffer solution,
but became very slow after the PVD hydrogel was formed [66]. The
pH-dependent sol-to-gel transformation of AEA was used to develop
nasal spray dosage forms for treating allergic rhinitis and sinusitis
[67]. The in vivo rat study showed that the apparent disappearance
rate constant of chlorpheniramine maleate decreased with increase
in the PVD concentration. The hydrogel formation on the mucous
membranes in the rat nasal cavity was visually conrmed. If the
time for sol-to-gel transition is shortened and the mucoadhesive
property is added, the PVD system could be an ideal system for
nasal delivery.
Hydrogels that are responsive to both temperature and pH can be
made by simply incorporating ionizable and hydrophobic (inverse
thermosensitive) functional groups to the same hydrogels. When a
small amount of anionic monomer, such as acrylic acid, is incorporated in a thermoreversible polymer, the LCST of the hydrogel depends
on the ionization of the pendant carboxyl groups, i.e. the pH of the
medium. As the pH of the medium increases above the pKa of the carboxyl groups of polyanions, LCST shifts to higher temperatures due to
the increased hydrophilicity and charge repulsion. Terpolymer hydrogels
made of NIPAAm, vinyl terminated polydimethylsiloxane macromer and
acrylic acid were used for the delivery of indomethacin and amylase
[36,68]. Other terpolymer hydrogels containing NIPAAm, acrylic acid
and 2-hydroxyethyl methacrylate were prepared for the pulsatile delivery of streptokinase and heparin as a function of stepwise pH and temperature changes [69,70].
3.3.2. Other applications
pH-sensitive hydrogels have also been used in making biosensors
and permeation switches [5]. The pH-dependent hydrogels for these
applications are usually loaded with enzymes that change the pH of
the local microenvironment inside the hydrogels. One of the common
enzymes used in pH-sensitive hydrogels is glucose oxidase which
transforms glucose to gluconic acid. The formation of gluconic acid
lowers the local pH, thus affecting the swelling of pH-dependent
hydrogels.

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Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

3.4. Limitations and improvements

One of the inherent limitations of synthetic pH-sensitive polymers
is their non-biodegradability. For this reason, hydrogels made of
non-biodegradable polymers have to be removed from the body after
use. The non-biodegradability is not a problem in certain applications,
such as in oral drug delivery, but it becomes a serious limitation in
other applications, such as the development of implantable drug delivery agents or implantable biosensors. Thus, attention has been focused
on the development of biodegradable, pH-sensitive hydrogels based on
polypeptides, proteins and polysaccharides [71,72]. Dextran was activated with 4-aminobutyric acid for crosslinking with 1,10-diaminodecane,
and also grafted with carboxylic groups [71]. The modied dextran
hydrogels showed a faster and higher degree of swelling at high pH
conditions, and changing the pH between 7.4 and 2.0 resulted in cyclic swellingdeswelling. It is noted that dextran hydrogels may not
be exactly biodegradable, since the body or certain sites in the body may
not have the enzyme to degrade dextran molecules. Natural polysaccharides are not necessarily biodegradable in the human body.
Synthetic polypeptides were also used in synthesis of biodegradable hydrogels because of their more regular arrangement and less
versatile amino acid residues than those derived from natural proteins. Examples of such synthetic polypeptide hydrogels include
poly(hydroxyl-L-glutamate), poly(L-ornithine), poly(aspartic acid),
poly(L-lysine) and poly(L-glutamic acid) [72]. In addition to normal
electrostatic effects associated with most pH-sensitive synthetic
polymer hydrogels, secondary structures of the polypeptide backbone may also contribute to the pH-sensitive swelling behavior
[72]. The overall extent of pH-responsive swelling could be engineered
by modication of the polypeptide by changing its hydrophobicity and
degree of ionization.
4. Glucose-sensitive hydrogels
One of the most challenging problems in controlled drug delivery
area is the development of self-regulated (modulated) insulin delivery systems. Delivery of insulin is different from delivery of other
drugs, since insulin has to be delivered in an exact amount at the
exact time of need. Thus, self-regulated insulin delivery systems
require the glucose sensing ability and an automatic shut-off mechanism. Many hydrogel systems have been developed for modulating
insulin delivery, and all of them have a glucose sensor built into the
system.
4.1. pH-sensitive membrane systems
Glucose oxidase is probably the most widely used enzyme in glucose
sensing. It oxidizes glucose to gluconic acid, resulting in a pH change of
the environment. This makes it possible to use different types of pHsensitive hydrogels for modulated insulin delivery. For hydrogel membranes made of polycations, such as PDEAEM, the lowering of pH
leads to hydrogel membrane swelling due to the ionization of PDEAEM.
When a membrane swells, it tends to release more drugs, including
insulin, than the membrane in the less-swollen state [73,74].
If the hydrogel membranes are made of polyanions, selfregulated insulin release is controlled by different mechanisms. A
glucose-sensitive hydraulic ow controller can be designed using
a porous membrane system consisting of a porous lter grafted
with polyanions, e.g. poly(methacrylic acidco-butyl methacrylate), and immobilized glucose oxidase. The grafted polyanion chains
are expanded at pH 7 due to electrostatic repulsion among the charges
on the polymer chains. When glucose oxidase converts glucose to
gluconic acid, however, the chains collapse due to the protonation of
the carboxyl groups of the polymer. Thus, the pores are open for the diffusion of insulin [75]. In another formulation, insulin can be loaded
inside a hydrogel matrix which can be collapsed (or shrunken) as a

result of lowering the pH. In this case, insulin release is enhanced due
to the squeezing action of the collapsing hydrogel [76]. In a system
where a glucose oxidase-containing hydrogel covers a pH-sensitive
erodible polymer that contains insulin, the polymer erosion, and thus
insulin release, is controlled by the lowering of the local pH [77].
4.2. Con A-immobilized systems
Concanavalin A (Con A) has also been frequently used in modulated
insulin delivery. Con A is a glucose-binding protein obtained from the
jack bean plant, Canavalia ensiformis. In this type of system, insulin molecules are attached to a support or carrier through specic interactions
which can be interrupted by glucose itself. This generally requires the
introduction of functional groups onto insulin molecules. In one approach, insulin was chemically modied to introduce glucose, which
themselves binds especially to Con A [78]. The glycosylated insulin
Con A system exploits the complementary and competitive binding
behavior of Con A with glucose and glycosylated insulin. The free glucose molecules compete with glucoseinsulin conjugates bound to
Con A and thus, the glycosylated insulin is desorbed from the Con A
host in the presence of free glucose. The desorbed glucoseinsulin
conjugates are released within the surrounding tissue, where studies
have shown that they are bioactive. Various glycosylated insulins
having different binding afnities to Con A have been synthesized in
an effort to manipulate the displacement of immobilized insulin from
Con A at different glucose levels [7984].
4.3. Solgel phase reversible hydrogel systems
Hydrogels can be made to undergo solgel phase transformations
depending on the glucose concentration in the environment. Reversible
solgel phase transformations require glucose-responsive crosslinking.
A highly specic interaction between glucose and Con A was used
to form crosslinks between glucose-containing polymer chains. Since
Con A exists as a tetramer at physiological pH and each subunit has a
glucose binding site, Con A can function as a crosslinking agent for
glucose-containing polymer chains. Because of the non-covalent interaction between glucose and Con A, the formed crosslinks are reversible,
as shown in Fig. 6 [8589]. As the external glucose molecules diffuse
into the hydrogel, individual free glucose molecules can compete with
the polymer-attached glucose molecules and exchange with them.
The concentrations of Con A and glucose-containing polymers can be
adjusted to make hydrogels that respond (i.e. undergo gel-to-sol transformation) at specic free glucose concentrations. It has been shown
that diffusion of insulin through the solution (Sol) phase is an
order of magnitude faster than that through the hydrogel (gel)
phase, and that insulin release can be controlled as a function of
the glucose concentration in the environment. Other similar systems
utilized poly(glucosyloxyethylmethacrylate)Con A complexes [90,91]
and polysaccharide (e.g. polysucrose, dextran, glycogen)Con A gel
membranes [9294].
Glucose-sensitive phase-reversible hydrogels can also be prepared
without using Con A. Polymers having phenylboronic groups (e.g. poly
[3-(acrylamido)phenylboronic acid] and its copolymers) and polyol
polymers (e.g. PVA) form a gel through complex formation between
the pendant phenylborate and hydroxyl groups, as shown in Fig. 7
[9597]. Glucose, having pendant hydroxyl groups, competes with
polyol polymers for the borate cross-linkages. Since glucose is
monofunctional (i.e. has only one binding site for the borate group), it
cannot function as a crosslinking agent as polyol polymer does. Thus,
as the glucose concentration increases, the crosslinking density of the
gel decreases and the gel swells/erodes to release more insulin. With
higher glucose concentrations, the gel becomes a sol. The glucose exchange reaction is reversible and borate-polyol crosslinking is reformed
at a lower glucose concentration. Instead of long chain polyol polymers,
shorter molecules, such as diglucosylhexanediamine, can be used as a

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55

Fig. 6. Solgel phase-transition of a glucose-sensitive hydrogel. Large circles represent Con A, a glucose-binding protein. Small open and closed hexagons represent polymer-attached glucose
and free glucose, respectively.

crosslinking agent. Since the phenylboronic acid gel is sensitive to glucose only at alkaline conditions (pH 9), various copolymers containing
phenylboronic acid were synthesized to provide glucose sensitivity at
physiological pH. The main problem of this system is the low specicity
of PBA-containing polymers to glucose.

4.4. Limitations and improvements

Although all of the glucose-sensitive insulin delivery systems are elegant and highly promising, many improvements need to be made for
them to become clinically useful. First of all, the response of these
hydrogels upon changes in the environmental glucose concentration occurs too slowly. Furthermore, hydrogels do not go back to their original
states fast enough after responding to the changing glucose concentration. Reducing the hydrogel dimensions may be one way of shortening
the response time. The current hydrogel systems also need improved reproducibility. In clinical situations, the hydrogels need to respond to ever
changing glucose concentrations all the time, requiring hydrogels that can
respond reproducibly and with rapid response onset times on a long-term
basis. An additional constraint is that all the components used in the
glucose-sensitive hydrogels should be biocompatible (e.g. Con A, the
crosslinker most frequently used in modulated insulin delivery, is
known to induce undesirable immune response [98,99]). Successful
clinical applications of glucose-sensitive hydrogels for modulated insulin
delivery demand new, biocompatible glucose-binding molecules.

5. Electric signal-sensitive hydrogels

5.1. Properties of electro-sensitive hydrogels
Electric current can also be used as an environmental signal to induce
responses of hydrogels. Hydrogels sensitive to electric current are usually
made of polyelectrolytes, as are pH-sensitive hydrogels. Electro-sensitive
hydrogels undergo shrinking or swelling in the presence of an applied
electric eld. Sometimes, the hydrogels show swelling on one side and
deswelling on the other side, resulting in bending of the hydrogels. The
hydrogel shape change (including swelling, shrinking and bending)
depends on a number of conditions. If the surface of hydrogel is in contact with the electrode, the result of applying electric eld to the hydrogel may be different from systems where the hydrogel is placed in water
(or acetonewater mixture) without touching the electrode. The result
will be different yet if the aqueous phase contains electrolytes.
Partially hydrolyzed polyacrylamide hydrogels which are in contact with both the anode and cathode electrodes undergo volume collapse by an innitesimal change in electric potential across the gel. It
should be noted that the hydrogels do not contain any salts. When the
potential is applied, hydrated H + ions migrate toward the cathode
resulting in loss of water at the anode side. At the same time, electrostatic attraction of negatively charged acrylic acid groups toward the
anode surface creates a uniaxial stress along the gel axis, mostly at the
anode side. These two simultaneous events lead to shrinking of the
hydrogel at the anode side [100,101].

Fig. 7. Solgel phase-transition of a phenylborate polymer. At alkaline pH, phenylborate polymer interacts with poly(vinyl alcohol) (PVA) to form a gel. Glucose replaces PVA to
induce a transition from the gel to the sol phase.

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Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

When a hydrogel made of sodium acrylic acidacrylamide copolymer

is placed in aqueous solution (acetonewater mixture) under electric
eld without touching the electrodes, the type of hydrogel deformation
depends on the concentration of the electrolytes. In the absence of electrolytes or in the presence of very low concentration of electrolytes,
application of an electric eld causes the hydrogel to shrink. This is due
to the migration of Na+ to the cathode electrode resulting in changes
in the carboxyl groups of the polymer chains from COO Na + to
COOH [102]. In the presence of high concentration of electrolytes in solution, however, more Na+ enters the hydrogel than migrates from the
hydrogel to the cathode [102]. The swelling is more prominent at the
hydrogel side facing the anode and this results in bending of the
hydrogels. If a cationic surfactant, such as n-dodecylpyridinium chloride, is added to the aqueous solution, the swelling occurs at the cathode
side of the hydrogel [10]. This is due to the movement of positively
charged surfactant molecules toward the cathode to form a complex
with the negatively charged polymer chains on the side of the hydrogel
facing the anode.
When microspherical hydrogel particles are placed in water without any salts, application of an electric eld results in the shrinkage of
the hydrogels due to electroosmosis (migration of water) and electrophoresis (migration of charged ions) from the hydrogel to the cathode [103]. This property has been used for modulated drug delivery
by onoff of the electric eld. As described above, the response of
electro-sensitive hydrogels depends on the experimental conditions
and thus, any generalization on the swelling/collapse behavior cannot
be made.

[9]. Those systems can serve as actuators or articial muscles in many

applications. All living organisms move by the isothermal conversion
of chemical energy into mechanical work, e.g. muscular contraction,
and agellar and ciliary movement. Electrically driven motility has
been demonstrated using weakly crosslinked poly(2-acrylamido-2methylpropanesulfonic acid) hydrogels. In the presence of positively
charged surfactant molecules, the surface of the polyanionic hydrogel
facing the cathode is covered with surfactant molecules reducing the
overall negative charge. This results in local shrinkage of the hydrogel
leading to bending of the hydrogel. Application of an oscillating electrode polarity could lead the hydrogel to quickly repeat its oscillatory
motion, leading to a worm-like motion [10].
5.2.3. Limitations and improvements
One of the advantages of electro-sensitive hydrogels in drug delivery
is that the drug release rate can be easily controlled simply by modulating the electric eld. At present, controlled drug delivery based on
electro-sensitive hydrogels is still in its infancy. Aside from the problem
common to all hydrogels, i.e. slow response of the hydrogel itself, the
use of electro-sensitive hydrogels requires a controllable voltage source.
In addition, most of the electro-sensitive hydrogels work in the absence
of electrolytes. It may not be easy to develop drug delivery modules
based on electro-sensitive hydrogels that work under physiological
conditions.
6. Light-sensitive hydrogels
6.1. Properties of light-sensitive hydrogels

5.2. Applications of electro-sensitive hydrogels

5.2.1. Applications in drug delivery
Electro-sensitive hydrogels have been applied in controlled
drug delivery [1,103]. Hydrogels made of poly(2-acrylamido-2methylpropane sulfonic acidco-n-butylmethacrylate) were able to
release edrophonium chloride and hydrocortisone in a pulsatile manner
using electric current [104]. Control of onoff drug release was achieved
by varying the intensity of electric stimulation in distilleddeionized
water. For edrophonium, a positively charged drug, the release pattern
was explained as an ion exchange between the positively-charged solute
and hydrogen ion produced by electrolysis of water.
Chemomechanical shrinking and swelling of PMA hydrogels under
an electric eld was used for the pulsatile delivery of pilocarpine and
rafnose. Microparticles of PAA hydrogel which showed rapid and
sharp shrinkage with the application of electric current, recovered
their original size when the electric eld was turned off. The electric
eld-induced changes in the size of the microparticles resulted in
onoff release proles. The electric eld-induced volume changes
of poly(dimethylaminopropyl acrylamide) hydrogels were used for
pulsatile release of insulin [103]. The monolithic device composed of
sodium alginate and PAA was also used to release hydrocortisone in
a pulsatile manner using an electric stimulus [105].
In addition to hydrogel swelling and contraction, electric elds
have also been used to control the erosion of hydrogels made of
poly(ethyloxazoline)PMA complex in a saline solution [106]. The
two polymers form a hydrogel via intermolecular hydrogen bonding
between carboxylic and oxazoline groups. When the gel matrix was
attached to a cathode surface, application of electric current caused disintegration of the complex into water-soluble polymers at the gel surface facing the cathode. The surface erosion of this polymer system
was controlled either in a stepwise or continuous fashion by controlling
the applied electrical stimulus. Pulsatile insulin release was achieved by
applying a step function of electric current.
5.2.2. Applications in other areas
Electro-sensitive hydrogels, which are basically pH-sensitive
hydrogels, are able to convert chemical energy to mechanical energy

Light-sensitive hydrogels have potential applications in developing

optical switches, display units, and opthalmic drug delivery devices.
Since the light stimulus can be imposed instantly and delivered in
specic amounts with high accuracy, light-sensitive hydrogels may
possess special advantages over others. For example, the sensitivity of
temperature-sensitive hydrogels is rate limited by thermal diffusion,
while pH-sensitive hydrogels can be limited by hydrogen ion diffusion.
The capacity for instantaneous delivery of the solgel stimulus makes
the development of light-sensitive hydrogels important for various
applications in both engineering and biochemical elds. Light-sensitive
hydrogels can be separated into UV-sensitive and visible light-sensitive
hydrogels. Unlike UV light, visible light is readily available, inexpensive,
safe, clean and easily manipulated.
The UV-sensitive hydrogels were synthesized by introducing a leuco
derivative molecule, bis(4-dimethylamino)phenylmethyl leucocyanide,
into the polymer network [107]. Triphenylmethane leuco derivatives
are normally neutral but dissociate into ion pairs under ultraviolet irradiation producing triphenylmethyl cations. As shown in Fig. 8, the leuco
derivative molecule can be ionized upon ultraviolet irradiation. At a
xed temperature, the hydrogels discontinuously swelled in response to
UV irradiation but shrank when the UV light was removed. The UVinduced discontinuous volume phase transition is different from a continuous volume phase transition in the absence of UV-irradiation. The UV
light-induced swelling was due to an increase in osmotic pressure within
the gel due to the appearance of cyanide ions formed by UV irradiation.
Visible light-sensitive hydrogels were prepared by introducing a
light-sensitive chromophore (e.g. trisodium salt of copper chlorophyllin)
to poly(N-isopropylacrylamide) hydrogels [108]. When light
(e.g. 488 nm) is applied to the hydrogel, the chromophore absorbs
light which is then dissipated locally as heat by radiationless transitions,
increasing the local temperature of the hydrogel. The temperature
increase alters the swelling behavior of poly(N-isopropylacrylamide)
hydrogels, which are thermo-sensitive hydrogels. The temperature
increase is proportional to the light intensity and the chromophore concentration. If an additional functional group, such as an ionizable group
of PAA, is added, the light-sensitive hydrogels become responsive to pH
changes also [109]. This type of hydrogel can be activated (i.e. induced

Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

57

Fig. 8. Structure of leuco derivative molecule bis(4-(dimethylamino)phenyl)(4-vinylphenyl)methylleucocyanide (from Ref. [107]).

to shrink) by visible light and can be deactivated (i.e. induced to swell)

by increasing pH.
Since the mechanism of the visible light-induced volume change of
these hydrogels is based on the induction of temperature changes via
the incorporated photosensitive molecules, infrared light can also be
used to elicit hydrogel response in the absence of the chromophores.
This method is useful due to the high infrared light absorbency of
water. When poly(N-isopropylacrylamide) hydrogels without any chromophores are irradiated by a CO2 laser infrared, the volume phase transition, together with a gel bending toward the laser beam was observed
during irradiation [110]. The degree of bending, due to the formation of a
temperature gradient, depended on the CO2 laser power, while the relaxation of the gel to its original shape after irradiation followed an exponential form.
6.2. Applications
Light-sensitive hydrogels can be used in the development of photoresponsive articial muscles, switches and memory devices [108]. The
potential application of visible light-responsive hydrogels for temporal
drug delivery was also proposed, based on the response of crosslinked
hyaluronic acid hydrogels that undergo photosensitized degradation
in the presence of methylene blue [111].
6.3. Limitations and improvements
While the action of stimulus (light) is instantaneous, the reaction of
hydrogels in response to such action is still slow. In most cases, the
conversion of light into thermal energy must precede the restructuring
of polymer chains upon temperature change. In addition, unless
chromophores are covalently linked to the polymer backbone, they
can be leached out during swellingdeswelling cycles.
7. Other stimuli sensitive hydrogels
In addition to the widely used stimuli discussed above, other stimuli
have also been used for making environmentally sensitive hydrogels.
Other stimuli include pressure [112], specic ions [113], thrombin
[114116] and antigen [117].
7.1. Pressure-sensitive hydrogels
The concept that hydrogels may undergo pressure-induced
volume phase transition came from thermodynamic calculations
based on uncharged hydrogel theory. According to the theory,
hydrogels which are collapsed at low pressure would expand at higher
pressure. Experiments with poly(N-isopropylacrylamide) hydrogels
conrmed this prediction [112]. The degree of swelling of poly
(N-isopropylacrylamide) hydrogels increased under hydrostatic pressure when the temperature is close to its LCST. Other hydrogels, such
as poly(N-n-propylacrylamide), poly(N,N-diethylacrylamide) and poly
(N-isopropylacrylamide), all showed the pressure sensitivity near
their LCSTs. The pressure sensitivity appeared to be a common characteristic of temperature-sensitive gels. It was concluded that the pressure sensitivity of the temperature-sensitive gels was due to an
increase in their LCST value with pressure [113].

7.2. Specic ion-sensitive hydrogels

Little or no effect of salt concentration on swelling behavior is expected for neutral hydrogels. A nonionic poly
(N-isopropylacrylamide) hydrogel, however, showed a sharp volume
phase transition at a critical concentration of sodium chloride in aqueous solution [118]. Below the LCST, the water content of the hydrogel
is a strong function of the sodium chloride concentration. The gel collapses sharply at a critical sodium chloride concentration; this concentration was also found to be temperature dependent. Increasing
temperatures leads to a corresponding decrease in the critical concentration of sodium chloride. Other salts tested show no such behavior
outside the salting-out regime. Sodium ions were common to all of
the salts tested, suggesting that chloride ions played a major role in
this phase transition. Although the mechanism for this unique
ion-sensitivity remained unknown, the LCST of the hydrogel appeared
to be lowered by increasing the chloride concentration. This unique
phase transition behavior could be applicable to making chloride
ion-sensitive biosensors.
The phase transition behavior of positively charged poly
(diallyldimethylammonium chloride) hydrogels is sensitive to the
concentration of sodium iodide [119]. At the critical concentration,
sodium iodide could induce a hydrogel to collapsed state phase transition, however, a wide hysteresis accompanies this transition. Since
other salts tested did not initiate the network collapse in the investigated concentration ranges, an ion pair and multiplet (ionomer
effect) theory was proposed to explain these interesting experimental
results.
7.3. Specic antigen-responsive hydrogels
For some biomedical applications, it is highly desirable and useful to
develop a material or device, which can response to specic proteins.
Solgel phase-reversible hydrogels were prepared based on antigen
antibody interactions. The concept is the same as that used in
glucose-sensitive phase-reversible hydrogels. A semi-interpenetrating
network hydrogel was prepared by grafting an antigen and a corresponding antibody to different polymer networks [117]. The gel is
formed by crosslinking interactions that occur upon antigenantibody
binding. Hydrogel swelling is triggered in the presence of free antigens
that compete with the polymer-bound antigen, leading to a reduction in
the crosslinking density (Fig. 9).
7.4. Thrombin-induced infection-responsive hydrogels
For release of antibiotics at the site and time of infection, PVA
hydrogels loaded with grafted gentamycin were made. Gentamycin
was chemically attached to the polymer backbone through peptide
linkers that can be enzymatically degraded by thrombin [114]. This
approach was based on the observation that exudates from the dorsal
pouch of rats infected by Pseudomonas aeruginosa showed signicantly higher thrombin-like enzymatic activity toward a certain peptide
sequence than exudates from non-infected wounds. This is the same
approach as the polymeric prodrugs that release attached drug molecules slowly, except that in this case, the release is accelerated by infection. This type of approach can be applied to occlusive wound

58

Y. Qiu, K. Park / Advanced Drug Delivery Reviews 64 (2012) 4960

Fig. 9. Swelling of an antigenantibody semi-IPN hydrogel in response to free antigen (from Ref. [117]).

dressings and infection-prone catheters, drainage bags and prostheses

[114]. This type of system in general has sufcient specicity and excellent potential as a stimulus-responsive, controlled drug release system
[116].
8. Summary
Environmentally-sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either
pH-sensitive and/or temperature sensitive hydrogels can be used for
site-specic controlled drug delivery. Hydrogels that are responsive to
specic molecules, such as glucose or antigens, can be used as bisensors
as well as drug delivery systems. Light-sensitive, pressure-responsive
and electro-sensitive hydrogels also have potential to be used in drug delivery and bioseparation. While the concepts of these environmentallysensitive hydrogels are sound, the practical applications require signicant improvements in the hydrogel properties. The most signicant
weakness of all these external stumuli-sensitive hydrogels is that their
response time is too slow. Thus, fast-acting hydrogels are necessary
and the easiest way of achieving this goal is to make thinner and smaller
hydrogels. This usually makes the hydrogel system too fragile and they
do not have the mechanical strength necessary in many applications.
Environmentally-sensitive hydrogels for drug delivery applications
also require biocompatibility. Synthesis of new polymers and
crosslinkers with more biocompatibility and better biodegradability
would be essential for successful applications. Development of
environmentally-sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into
the future, however, it is highly likely that responsive hydrogels with
a wide array of desirable properties can be made.
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